An optimization algorithm for maximum quasi-clique problem based on information feedback model.

The maximum clique problem in graph theory is a well-known challenge that involves identifying the complete subgraph with the highest number of nodes in a given graph, which is a problem that is hard for nondeterministic polynomial time (NP-hard problem). While finding the exact application of the maximum clique problem in the real world is difficult, the relaxed clique model quasi-clique has emerged and is widely applied in fields such as bioinformatics and social network analysis. This study focuses on the maximum quasi-clique problem and introduces two algorithms, NF1 and NR1. These algorithms make use of previous iteration information through an information feedback model, calculate the information feedback score using fitness weighting, and update individuals in the current iteration based on the benchmark algorithm and selected previous individuals. The experimental results from a significant number of composite and real-world graphs indicate that both algorithms outperform the original benchmark algorithm in dense instances, while also achieving comparable results in sparse instances.

Tetramethylpyrazine Nitrone (TBN) Reduces Amyloid ß Deposition in Alzheimer's Disease Models by Modulating APP Expression, BACE1 Activity, and Autophagy Pathways.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid ß (Aß) aggregates result from dyshomeostasis between Aß production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aß reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aß, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aß deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 µM) to explore the mechanism of TBN in Aß reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aß deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-ß, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aß levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

Tetramethylpyrazine nitrone delays the aging process of C. elegans by improving mitochondrial function through the AMPK/mTORC1 signaling pathway.

Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.

Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1G93A transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1ß/NF-κB pathways.

AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. METHODS: A-1 at 33.3 mg/kg was administrated in SOD1G93A transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. RESULTS: A-1 administration in SOD1G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1ß, pIκBα/IκBα, and pNF-κB/NF-κB. CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1ß/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.

Advances in Clinical Therapies for Huntington's Disease and the Promise of Multi-Targeted/Functional Drugs Based on Clinicaltrials.gov.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects. While gene therapies, such as antisense oligonucleotides, small interfering RNAs and gene editing, have emerged in the field of HD treatment, their safety and efficacy are still under debate. Therefore, pharmacological therapy remains the most promising breakthrough, especially multi-target/functional drugs, which have diverse pharmacological effects. This review summarizes the latest progress in HD drug development based on clinicaltrials.gov search results (Search strategy: key word "Huntington's disease" in HD clinical investigational drugs registered as of December 31, 2023), and highlights the key role of multi-target/functional drugs in HD treatment strategies.

Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin-Proteasome System Activation.

Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin-proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αß and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN's effects on Psmb8, Pa28αß, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.

Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.

Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1ß, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.

Genome-Wide Identification and Characterization of Long Non-Coding RNAs in Roots of Rice Seedlings under Nitrogen Deficiency.

Long non-coding RNAs (lncRNAs) regulate gene expression in eukaryotic organisms. Research suggests that lncRNAs may be involved in the regulation of nitrogen use efficiency in plants. In this study, we identified 1628 lncRNAs based on the transcriptomic sequencing of rice roots under low-nitrogen (LN) treatment through the implementation of an integrated bioinformatics pipeline. After 4 h of LN treatment, 50 lncRNAs and 373 mRNAs were significantly upregulated, and 17 lncRNAs and 578 mRNAs were significantly downregulated. After 48 h LN treatment, 43 lncRNAs and 536 mRNAs were significantly upregulated, and 42 lncRNAs and 947 mRNAs were significantly downregulated. Moreover, the interaction network among the identified lncRNAs and mRNAs was investigated and one of the LN-induced lncRNAs (lncRNA24320.6) was further characterized. lncRNA24320.6 was demonstrated to positively regulate the expression of a flavonoid 3'-hydroxylase 5 gene (OsF3'H5). The overexpression of lncRNA24320.6 was shown to improve nitrogen absorption and promote growth in rice seedlings under LN conditions. Our results provide valuable insights into the roles of lncRNAs in the rice response to nitrogen starvation.

Identification of Superior Haplotypes and Haplotype Combinations for Grain Size- and Weight-Related Genes for Breeding Applications in Rice (Oryza sativa L.).

The identification of superior haplotypes and haplotype combinations is essential for haplotype-based breeding (HBB), which provides selection targets for genomics-assisted breeding. In this study, genotypes of 42 functional genes in rice were analyzed by targeted capture sequencing in a panel of 180 Indica rice accessions. In total, 69 SNPs/Indels in seven genes were detected to be associated with grain length (GL), grain width (GW), ratio of grain length-width (L/W) and thousand-grain weight (TGW) using candidate gene-based association analysis, including BG1 and GS3 for GL, GW5 for GW, BG1 and GW5 for L/W, and AET1, SNAC1, qTGW3, DHD1 and GW5 for TGW. Furthermore, two haplotypes were identified for each of the seven genes according to these associated SNPs/Indels, and the amount of genetic variation explained by different haplotypes ranged from 3.24% to 27.66%. Additionally, three, three and eight haplotype combinations for GL, L/W and TGW explained 25.38%, 5.5% and 22.49% of the total genetic variation for each trait, respectively. Further analysis showed that Minghui63 had the superior haplotype combination Haplotype Combination 4 (HC4) for TGW. The most interesting finding was that some widely used restorer lines derived from Minghui63 also have the superior haplotype combination HC4, and our breeding varieties and lines using the haplotype-specific marker panel also confirmed that the TGW of the lines was much higher than that of their sister lines without HC4, suggesting that TGW-HC4 is the superior haplotype combination for TGW and can be utilized in rice breeding.

Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson's disease models.

INTRODUCTION: Parkinson's disease (PD) is common neurodegenerative disease where oxidative stress and mitochondrial dysfunction play important roles in its progression. Tetramethylpyrazine nitrone (TBN), a potent free radical scavenger, has shown protective effects in various neurological conditions. However, the neuroprotective mechanisms of TBN in PD models remain unclear. OBJECTIVES: We aimed to investigate TBN's neuroprotective effects and mechanisms in PD models. METHODS: TBN's neuroprotection was initially measured in MPP+/MPTP-induced PD models. Subsequently, a luciferase reporter assay was used to detect peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promoter activity. Effects of TBN on antioxidant damage and the PGC-1α/Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway were thoroughly investigated. RESULTS: In MPP+-induced cell model, TBN (30-300 µM) increased cell survival by 9.95 % (P < 0.05), 16.63 % (P < 0.001), and 24.09 % (P < 0.001), respectively. TBN enhanced oxidative phosphorylation (P < 0.05) and restored PGC-1α transcriptional activity suppressed by MPP+ (84.30 % vs 59.03 %, P < 0.01). In MPTP-treated mice, TBN (30 mg/kg) ameliorated motor impairment, increased striatal dopamine levels (16.75 %, P < 0.001), dopaminergic neurons survival (27.12 %, P < 0.001), and tyrosine hydroxylase expression (28.07 %, P < 0.01). Selegiline, a positive control, increased dopamine levels (15.35 %, P < 0.001) and dopaminergic neurons survival (25.34 %, P < 0.001). Additionally, TBN reduced oxidative products and activated the PGC-1α/Nrf2 pathway. PGC-1α knockdown diminished TBN's neuroprotective effects, decreasing cell viability from 73.65 % to 56.87 % (P < 0.001). CONCLUSION: TBN has demonstrated consistent effectiveness in MPP+-induced midbrain neurons and MPTP-induced mice. Notably, the therapeutic effect of TBN in mitigating motor deficits and neurodegeneration is superior to selegiline. The neuroprotective mechanisms of TBN are associated with activation of the PGC-1α/Nrf2 pathway, thereby reducing oxidative stress and maintaining mitochondrial function. These findings suggest that TBN may be a promising therapeutic candidate for PD, warranting further development and investigation.

Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

Iterated Clique Reductions in Vertex Weighted Coloring for Large Sparse Graphs.

The Minimum Vertex Weighted Coloring (MinVWC) problem is an important generalization of the classic Minimum Vertex Coloring (MinVC) problem which is NP-hard. Given a simple undirected graph G=(V,E), the MinVC problem is to find a coloring s.t. any pair of adjacent vertices are assigned different colors and the number of colors used is minimized. The MinVWC problem associates each vertex with a positive weight and defines the weight of a color to be the weight of its heaviest vertices, then the goal is the find a coloring that minimizes the sum of weights over all colors. Among various approaches, reduction is an effective one. It tries to obtain a subgraph whose optimal solutions can conveniently be extended into optimal ones for the whole graph, without costly branching. In this paper, we propose a reduction algorithm based on maximal clique enumeration. More specifically our algorithm utilizes a certain proportion of maximal cliques and obtains lower bounds in order to perform reductions. It alternates between clique sampling and graph reductions and consists of three successive procedures: promising clique reductions, better bound reductions and post reductions. Experimental results show that our algorithm returns considerably smaller subgraphs for numerous large benchmark graphs, compared to the most recent method named RedLS. Also, we evaluate individual impacts and some practical properties of our algorithm. Furthermore, we have a theorem which indicates that the reduction effects of our algorithm are equivalent to that of a counterpart which enumerates all maximal cliques in the whole graph if the run time is sufficiently long.

Comprehensive identification and characterization of lncRNAs and circRNAs reveal potential brown planthopper-responsive ceRNA networks in rice.

Brown planthopper (Nilaparvata lugens Stål, BPH) is one of the most destructive pests of rice. Non-coding RNA plays an important regulatory role in various biological processes. However, comprehensive identification and characterization of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in BPH-infested rice have not been performed. Here, we performed a genome-wide analysis of lncRNAs and circRNAs in BPH6-transgenic (resistant, BPH6G) and Nipponbare (susceptible, NIP) rice plants before and after BPH feeding (early and late stage) via deep RNA-sequencing. A total of 310 lncRNAs and 129 circRNAs were found to be differentially expressed. To reveal the different responses of resistant and susceptible rice to BPH herbivory, the potential functions of these lncRNAs and circRNAs as competitive endogenous RNAs (ceRNAs) were predicted and investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Dual-luciferase reporter assays revealed that miR1846c and miR530 were targeted by the lncRNAs XLOC_042442 and XLOC_028297, respectively. In responsive to BPH infestation, 39 lncRNAs and 21 circRNAs were predicted to combine with 133 common miRNAs and compete for miRNA binding sites with 834 mRNAs. These mRNAs predictably participated in cell wall organization or biogenesis, developmental growth, single-organism cellular process, and the response to stress. This study comprehensively identified and characterized lncRNAs and circRNAs, and integrated their potential ceRNA functions, to reveal the rice BPH-resistance network. These results lay a foundation for further study on the functions of lncRNAs and circRNAs in the rice-BPH interaction, and enriched our understanding of the BPH-resistance response in rice.

Multiomics analysis of human peripheral blood reveals marked molecular profiling changes caused by one night of sleep deprivation.

Sleep insufficiency is associated with various disorders; the molecular basis is unknown until now. Here, 14 males and 18 females were subjected to short-term (24 h) sleep deprivation, and donated fasting blood samples prior to (day 1) and following (days 2 and 3) short-term sleep deprivation. We used multiple omics techniques to examine changes in volunteers' blood samples that were subjected to integrated, biochemical, transcriptomic, proteomic, and metabolomic analyses. Sleep deprivation caused marked molecular changes (46.4% transcript genes, 59.3% proteins, and 55.6% metabolites) that incompletely reversed by day 3. The immune system in particular neutrophil-mediated processes associated with plasma superoxidase dismutase-1 and S100A8 gene expression was markedly affected. Sleep deprivation decreased melatonin levels and increased immune cells, inflammatory factors and c-reactive protein. By disease enrichment analysis, sleep deprivation induced signaling pathways for schizophrenia and neurodegenerative diseases enriched. In sum, this is the first multiomics approach to show that sleep deprivation causes prominent immune changes in humans, and clearly identified potential immune biomarkers associated with sleep deprivation. This study indicated that the blood profile following sleep disruption, such as may occur among shift workers, may induce immune and central nervous system dysfunction.

Chrysin prevents inflammation-coinciding liver steatosis via AMPK signalling.

OBJECTIVES: We aimed to elucidate the therapeutic potential of Chrysin (CN) against the high-fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) and its mechanism. METHODS: To assess the hypothesis, NAFLD was induced in C57BL/6 mice by feeding a high-fat diet for up to two months, followed by CN administration (for three months). Liver injury/toxicity, lipid deposition, inflammation and fibrosis were detected via molecular and biochemical analysis, including blood chemistry, immunoimaging and immunoblotting. Moreover, we performed proteomic analysis to illuminate Chrysin's therapeutic effects further. KEY FINDINGS: CN treatment significantly reduced liver-fat accumulation and inflammation, ultimately improving obesity and liver injury in NAFLD mice. Proteomic analysis showed that CN modified the protein expression profiles in the liver, particularly improving the expression of proteins related to energy, metabolism and inflammation. Mechanistically, CN treatment increased AMP-activated protein and phosphorylated CoA (P-ACC). Concurrently, it reduced inflammation and inflammation activation by inhibiting NLRP3 expression. CONCLUSIONS: In summary, CN treatment reduced lipid metabolism by AMPK and inflammasome activation by NLRP3 inhibition, ultimately improving NAFLD progression. These findings suggest that CN could be a potential treatment candidate for the NFLAD condition.

Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.

BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells. RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice. CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.

Acetylated tau exacerbates learning and memory impairment by disturbing with mitochondrial homeostasis.

Increased tau acetylation at K274 and K281 has been observed in the brains of Alzheimer's disease (AD) patients and animal models, and mitochondrial dysfunction are noticeable and early features of AD. However, the effect of acetylated tau on mitochondria has been unclear until now. Here, we constructed three type of tau forms, acetylated tau mutant by mutating its K274/K281 into Glutamine (TauKQ) to mimic disease-associated lysine acetylation, the non-acetylation tau mutant by mutating its K274/K281 into Arginine (TauKR) and the wild-type human full-length tau (TauWT). By overexpression of these tau forms in vivo and in vitro, we found that, TauKQ induced more severe cognitive deficits with neuronal loss, dendritic plasticity damage and mitochondrial dysfunctions than TauWT. Unlike TauWT induced mitochondria fusion, TauKQ not only induced mitochondria fission by decreasing mitofusion proteins, but also inhibited mitochondrial biogenesis via reduction of PGC-1a/Nrf1/Tfam levels. TauKR had no significant difference in the cognitive and mitochondrial abnormalities compared with TauWT. Treatment with BGP-15 rescued impaired learning and memory by attenuation of mitochondrial dysfunction, neuronal loss and dendritic complexity damage, which caused by TauKQ. Our data suggested that, acetylation at K274/281 was an important post translational modification site for tau neurotoxicity, and BGP-15 is a potential therapeutic drug for AD.

Deep Learning of Phase-Contrast Images of Cancer Stem Cells Using a Selected Dataset of High Accuracy Value Using Conditional Generative Adversarial Networks.

Artificial intelligence (AI) technology for image recognition has the potential to identify cancer stem cells (CSCs) in cultures and tissues. CSCs play an important role in the development and relapse of tumors. Although the characteristics of CSCs have been extensively studied, their morphological features remain elusive. The attempt to obtain an AI model identifying CSCs in culture showed the importance of images from spatially and temporally grown cultures of CSCs for deep learning to improve accuracy, but was insufficient. This study aimed to identify a process that is significantly efficient in increasing the accuracy values of the AI model output for predicting CSCs from phase-contrast images. An AI model of conditional generative adversarial network (CGAN) image translation for CSC identification predicted CSCs with various accuracy levels, and convolutional neural network classification of CSC phase-contrast images showed variation in the images. The accuracy of the AI model of CGAN image translation was increased by the AI model built by deep learning of selected CSC images with high accuracy previously calculated by another AI model. The workflow of building an AI model based on CGAN image translation could be useful for the AI prediction of CSCs.